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      A NEW MEDIUM‐TERM BIOASSAY SYSTEM FOR DETECTION OF ENVIRONMENTAL CARCINOGENS USING DIETHYLNITROSAMINE‐INITIATED RAT LIVER FOLLOWED BY D‐GALACTOSAMINE TREATMENT AND PARTIAL HEPATECTOMY

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          Abstract

          The effects of D‐galactosamine on induction of preneoplastic glutathione S‐transferase placental form positive liver foci were investigated in F344 rats pretreated with diethylnitrosamine (DEN) in an attempt to improve the predictive value of the medium‐term bioassay system developed in our laboratory. Two weeks after the initial single ip dose (200 mg/kg) of DEN, administration of test compounds was commenced simultaneously with an ip injection of D‐galactosamine at a dose of 300 mg/kg body wt. All rats were then subjected to two‐thirds partial hepatectomy (PH) at week 5 and sacrificed for assessment of lesion yield at week 8. Measurement and comparison of the numbers and areas of glutathione S‐transferase placental form positive (GST‐P +) foci per cm 2 revealed a positive response to more carcinogens, including non‐hepatocarcinogens, than did the same bioassay system without injection of D‐galactosamine. Thus the results suggest that inclusion of this extra proliferative stimulus may improve the medium‐term detection of carcinogens and modifiers.

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          Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats--an approach for a new medium-term bioassay system.

          A large series of assays of the hepatocarcinogenic potential of 112 different compounds were carried out using a rapid bioassay system developed in this laboratory based on the two-step concept of hepatocarcinogenesis. Rats were initially given a single dose (200 mg/kg) of diethylnitrosamine (DEN) i.p. and starting 2 weeks later were treated with test compounds for 6 weeks and then killed, all rats being subjected to two-thirds partial hepatectomy (PH) at week 3. Carcinogenic potential was scored by comparing the number and area per cm2 of induced glutathione S-transferase placental form-positive (GST-P+) foci in the liver with those of the corresponding control group given DEN alone. Positive was scored for a significant increase in the value of GST-P+ foci, negative for no change or a decrease. Results were compared to reported Salmonella/microsome and long-term carcinogenicity test findings. Of the liver carcinogens, 10 out of 11 (90.9%) mutagenic, and 11 out of 13 (84.6%) non-mutagenic compounds gave positive results (mean, 87.5%). Carcinogens other than the hepatocarcinogens gave less positive results (two out of 17, 11.8%). None of the compounds reported as non-carcinogenic demonstrated positivity suggesting that the assay system does not suffer from the disadvantage of false-positive results. The protocol system also provided information concerning the inhibitory potential of compounds such as anti-oxidants. It is concluded that the present experimental protocol which requires far fewer animals and shorter duration than a long-term carcinogenicity test has practical applications for the rapid and economical screening of environmental hepatocarcinogens and their inhibitory agents.
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            Purification, induction, and distribution of placental glutathione transferase: a new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis.

            A polypeptide of Mr 26,000 and pI 6.7 that was markedly increased in rat livers bearing hyperplastic nodules (HNs) induced by chemical carcinogens was identified immunochemically as the subunit of neutral glutathione (GSH) transferase (GSHTase; RX:glutathione R-transferase, EC 2.5.1.18; also called GSH S-transferase) purified from placenta (GSHTase-P) and was demonstrated immunohistochemically to be localized in preneoplastic foci and HNs. In the present study, GSHTase-P has been purified from the HN-bearing liver, and the distribution and inducibility have been examined quantitatively using anti-GSHTase-P antibody. Elevation of GSHTase-P in the HN-bearing livers was also confirmed by in vitro translation of mRNAs isolated from the HN-bearing livers. The purified GSHTase-P was homogeneous in size but had two charge isomers on two-dimensional gel electrophoresis. In normal tissues, including liver, placenta, and fetal liver, the protein content of GSHTase-P was generally low but was significantly high in kidney and pancreas. In contrast, the amount of GSHTase-P in HN-bearing livers (primary hepatomas) and transplantable Morris hepatoma 5123D were several 10-fold higher than that in normal liver but were undetectably low in transplantable Yoshida ascites hepatoma AH 130. Different from ordinary drug-metabolizing enzymes, GSHTase-P was uninducible by administration of drugs and carcinogens prior to appearance of the preneoplastic foci and HNs. In addition, species specificity of GSHTase-P was low as it was crossreactive among rat, hamster, and human.
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              Experimental hepatitis induced by D-galactosamine.

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                Author and article information

                Journal
                Jpn J Cancer Res
                Jpn. J. Cancer Res
                10.1111/(ISSN)1349-7006a
                CAS
                Japanese Journal of Cancer Research : Gann
                Blackwell Publishing Ltd (Oxford, UK )
                0910-5050
                1876-4673
                May 1988
                : 79
                : 5 ( doiID: 10.1111/cas.1988.79.issue-5 )
                : 573-575
                Affiliations
                [ 1 ]First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho‐cho, Mizuho‐ku, Nagoya 467
                Article
                CAE573
                10.1111/j.1349-7006.1988.tb00023.x
                5917556
                3136108
                36c0df3f-d433-4cbc-bc38-37375f22abaa
                History
                Page count
                References: 10, Pages: 3
                Categories
                Rapid Communication
                Custom metadata
                2.0
                May 1988
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.6.9 mode:remove_FC converted:04.11.2015

                d‐galactosamine,medium‐term bioassay,partial hepatectomy,rat liver,gst‐p

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